ZA200408737B - combination of organic compounds. - Google Patents

combination of organic compounds. Download PDF

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ZA200408737B
ZA200408737B ZA200408737A ZA200408737A ZA200408737B ZA 200408737 B ZA200408737 B ZA 200408737B ZA 200408737 A ZA200408737 A ZA 200408737A ZA 200408737 A ZA200408737 A ZA 200408737A ZA 200408737 B ZA200408737 B ZA 200408737B
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South Africa
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disease
diabetic
group
renal
diuretic
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ZA200408737A
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Suraj Shivappa Shetty
Randy Lee Webb
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Description

Combination of Organic Compounds
The present invention relates to a combination of organic compounds that are antihypertensive agents with complementary modes of action for eliciting blood pressure- lowering, and also for attenuating the varied pathological sequelae of hypertension and several other cardiovascular disorders. Furthermore, this invention addresses the disparate responsiveness of humans to antihypertensive monotherapy, based on age and/or ethnicity (Campo C, Segura J, Ruilope LM, J Clin Hypertens (Greenwich) 2002 Jan, 4(1):35-40).
Finally, the choice of agents and their respective dosages in the combination regimen are designed to enhance tolerability by minimizing the risk of dose-dependent adverse effects associated with individual agents.
Numerous clinical studies have shown that lowering blood pressure in hypertensive patients reduces mortality and morbidity (Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH,
Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH, Lancet 1990, 335(8693):827-38). Despite the availability and use of various classes of agents in the treatment of this medical condition, adequate contre! of blood pressure is not always achieved (Waeber B, Brunner HR, Am J Hypertens 1997, 10(7 Pt 2):1315-137S). Using a combination of agents is one way to achieve the desired therapeutic end-point. An arbitrary : selection of antihypertensive agents of different classes for inclusion in a combination therapy regimen does not necessarily help achieve target levels of blood pressure in hypertensive mammals including humans (MacGregor GA, Markandu ND, Banks RA,
Bayliss J, Roulston JE, Jones JC, Br Med J (Clin Res Ed), 284(631 7):693-6). Therefore, a need for further development of methods of treatment, combinations, and pharmaceutical compositions clearly exists.
Specifically, the present invention relates to pharmaceutical compositions comprising (i) an angiotensin receptor (Type 1, AT) blocker (ARB) selected from the group consisting of . candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan, E-4177, SC-52458, and ZD8731, and pharmaceuticaily acceptable : salts thereof; (ii) a calcium channel! blocker {CCB} selected from the group consisting of amlodipine, felodipine, isradipine, iacidipine, nicardipine, nifedipine, niguidipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, ryosidine, anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamine, tiapamil, and verapamil, and pharmaceutically acceptable salts thereof; and, (iii) a diuretic selected from the group ) consisting of bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, spironolactone, triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, ’ methylchlorothiazide, metolazone, and dichlorphenamide, and pharmaceutically acceptable salts thereof where appropriate, i.e. if the diuretic compound is not already present as a pharmaceutically acceptable salt as e.g. in the case of hydrochlorothiazide; optionally in the presence of a pharmaceutically acceptable carrier. The invention further provides methods for treating hypertension and a variety of cardiovascular disorders enumerated below and their sequelae by administration of the pharmaceutical composition comprising (i) an angiotensin receptor blocker (ARB), (ii) a calcium channel blocker (CCB), (iii) and a diuretic to a mammal including humans.
Thus, the invention further relates to a pharmaceutical composition or a kit of parts, e.g. for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke which composition (or kit of part) comprises (i) an ARB selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan, E-4177, SC- 52458, and ZD8731, or a pharmaceutically acceptable salt thereof; and (ii) a CCB selected
A from the group consisting of amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, and . ryosidine, which all belong to the group of dihydropyridines (DHPs) and the non-DHP CCBs anipamii, dittiazerr, fendiiine, ‘iunarizine, gallopamii, mibefraail, prenyiamine, tiapamii, and verapamil, or a pharmaceutically acceptable salt thereof; and (iii) a diuretic selected from the group consisting of bumetanide, ethacrynic acid, furosemide, torsemide, amiloride,
spironolactone, triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide, ) hydrofiumethiazide, methylchiorothiazide, metclazone, and dichlorphenamide, or, where appropriate, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
A further aspect of the present invention is a method for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atria! flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction: {such as Alzheimer's), glaucoma and stroke, comprising administering a therapeutically effective amount of combination of (i) an
ARB selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan, E-4177, SC-52458, and
ZD8731, or a pharmaceutically acceptable salt thereof; and (ii) a CCB selected from the group consisting of amlodipine, feledipine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, and ryosidine, which all belong to the group of dihydropyridines {DHPs) and the non-DHP CGBs anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamine, tiapamil, and verapamil, or a pharmaceutically acceptable salt thereof, and (ii}) a diuretic selected from the group consisting of bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, spironolactone, triamterene, chiorothalidone, chiorothiazide, hydrochlorothiazide, hydroflumethiazide, 3 methylchlorothiazide, metolazone, and dichlorphenamide, or, where appropriate, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrierto a . mammal in need of such treatment.
The invention also relates to combining separate pharmaceutical compositions in kit form,
That is a kit combining twc or three separate units: e.g. a pharmaceutical composition comprising an ARB, an pharmaceutical composition comprising a CCB, and a ) pharmaceutical composition comprising 2 diuretic; or a charmaceutica! composition comprising an ARB and a diuretic, and a pharmaceutical composition comprising a CCB; or ) a pharmaceutical composition comprising a CCB and a diuretic, and a pharmaceutical composition comprising an ARB. Although the kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. parenteral valsartan formulation and oral amlodipine or hydrochiorothiazide formulations) or are administered at different dosage intervais, the administration of the single components of such a kit of parts may, without any restriction be effected simultaneously, sequentially or staggered with time.
In a preferred embodiment, the (commercial) product is a commercial package comprising as active ingredients the combination according to the present invention (in the form of two or three separate units of the components (i) to (iii), together with instructions for its simul- taneous, separate or sequential use, or any combination thereof, in the delay of progression or treatment of the diseases menticned herein. A preferred commercial package, is where the ARB (i) and the diuretic (iii) are present in the form of Co-DIOVAN @, or where the ACE inhibitor (i), the CCB (ii) and the diuretic (fii) are present in the form of Co-DIOVAN ® and
NORVASC ®.
The pharmaceutical preparations of the present invention are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances. For example, the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compounds. Pharmaceutical preparations for enteral or parenteral administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner, which is known per se, for example using . conventional mixing, granulation, coating, solubulizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active , compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if requirec cr necessary, processing the mixture or granuiate inic tabieis or coatec tablet cores after having added suitable auxiliary substances.
The dosage of the active compound can depend on a variety of factors, such as mode of ; administration, homeocthermic species, age and/or individual condition, Preferred dosages for the active ingredients of the pharmaceutical combination according to the present ) invention are therapeutically effective dosages, especiaily those that are commercially available. Normally, in the case of oral administration, an approximate daily dose of from about 20 mg to about 900 mg of active agents, i.e. ARB plus CCB plus diuretic, is to be estimated e.g. for a patient of approximately 75 kg in weight.
In the present invention preferred ARBs are those agents that have been marketed, as e.g. valsartan and losartan. The same applies to the CCBs employed in the present invention, of which amlodipine and felodipine are preferred. The most preferred diuretic is hydrochlorothiazide (HCTZ).
Very surprisingly is the finding that, a combination of (i) an ARB, (ii) a CCB, and (iii) a diuretic and in particular a combination comprising valsartan, amlodipine and HCTZ achieves greater therapeutic effect thar the administration: of valsartan, amlodipine, or HCTZ alone or in a combination: of two of these agents. Greater efficacy can aisc be documented as a prolonged duration of action. The duration of action can be monitored as either the time to return to baseline prior to the next dose or as the area under the curve (AUC) and is expressed as the product of the change in blood pressure in millimeters of mercury (change in mmHg) and the duration of the effect (minutes, hours or days). The aforementioned combination treatment also unexpectedly reduces blood pressure in hypertensive mammals in a smooth and sustained fashion. The trough:peak blood pressure ratio demonstrated by this combination is close to unity leading to a more homogenous blood pressure control during the inter-dosing period. The combined regimen is almost completely devoid of either orthostatic hypotension or first-dose hypotension, and incidences of rebound hypertension after cessation of treatment are very rare. it can be shown that combination therapy according to the invention results in lessening of pulse pressure in hypertensive mammals.
Furthermore, this combination therapy can ameliorate endothelial dysfunction and improve , vascular compliance and distensibility in hypertensive mammals. It can also slow the progression cf cardiac, renal and cereprai enc-crgar damage ir these mammais. ~urther benefits are that lower doses of the individual drugs tc be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used to diminish the ’ incidence cf side effects. Surprisingly, the combination of valsartan, amlodinine and HCTZ significantly reduce the incidences of peripheral edema relative to those observed in mammals treated with amlodipine alone. Aiso, the undesirable effects of HCTZ on serum lipids, glucose, and uric acid levels are surprisingly attenuated in mammals treated with the combined regimens of valsartan, amlodipine and HCTZ.
In particular the combined administration of valsartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and HCTZ results in a significant response in a greater percentage of treated patients compared to monotherapy or combination therapy e.g. valsartan and HCTZ, that is, a greater responder rate results, regardless of the underlying etiology of the condition. This is in accordance with the desires and requirements of the patients to be treated. The combination treatment effectively lowers blood pressure in hypertensive patients in all age groups including pre and postmenopausal women. It can be shown that combination therapy with valsartan, amlodipine, and HCTZ results in a more effective antihypertensive therapy (whether for malignant, essentia!, reno- vascular, diabetic, isolated systolic, or other secondary type of hypertension) and iessening of pulse pressure through improved efficacy. The combination is also useful in the treatment or prevention of heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter or detrimental vascular remodeling. It can further be shown that a valsartan, amlodipine, and HCTZ combination therapy proves to be beneficial in the treatment and prevention of myocardial infarction and its sequelae. A valsartan, amlodipine, and HCTZ combination is also useful in treating atherosclerosis, angina (whether stable or unstable), renal insufficiency (diabetic and non-diabetic), peripheral vascular disease, cognitive dysfunction, and stroke.
Furthermore, the improvement in endothelial function with the combination therapy using valsartan, amlodipine, and HCTZ provides benefit in diseases in which normal endothelial } function is disrupted such as heart failure, angina pectoris and diabetes. Furthermore, the combination of the present invention may be used for the treatment or prevention of , secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nepnrogatny, gicmeruioneprritis, sciercderme, giomeruiar sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as ' Alzheimer's}, glaucoma and stroke. The combination regimen alse surpricingly reduces the rate of progression of cardiac, renal and cerebral end-organ damage. By providing enhanced ’ efficacy, safety and tolerability, the combination of drugs indicated in this invention also has the potential to promote patient compliance, a major consideration in the pharmacological treatment of hypertension.
The person skilled in the pertinent art is fully enabled to select a relevant test model to prove the efficacy of a combination of the present invention in the herein before and hereinafter indicated therapeutic indications.
The advantages of the present combinations are, for example, demonstrated in a clinical study or in the test procedure as essentially described hereinafter. Many clinical study protocols adapted to test our combinations are known by the person skilled in the art.
An example of a clinical trial useful to demonstrate the unexpected advantages of our new combinations is described by Waeber B et a!. {J Hypertens. 200 Nov;19(11):2097-104. The same protocol is performed with our preferred combinations such as a combination, preferably fixed-dose combination, of valsartan 80mg, hydrochlorothiazide 12.5 mg, and amlodipine 5 mg. This protocol is hereby incorporated into the present application by reference to this publications.
Representative studies are carried out with a combination of valsartan, amlodipine, and
HCTZ applying the following methodology. Drug efficacy is assessed in various animal models including the deoxycorticosterone acetate - salt rat (DOCA-salt) and the spontaneously hypertensive rat (SHR), either maintained on a normal salt diet or with salt loading (4-8% salt in rat chow or 1% NaCl as drinking water).
The DOCA-salt test model utilizes either an acute or chronic study protocol. An acute study . procedure involves assessment of the effects of various test substances over a six-hour experimental period using rats with indwelling femoral arterial and venous catheters. The . Acute Study Procedure evaluates test substances for their ability to reduce blood pressure during the established phase =f DOCA-sait nyperiensicn. In contrast, the Shrenic Stucy
Procedure assesses the ability of test substances to prevent or delay the rise in blood pressure during the development phase of DOCA-salt hypertension. Therefore, blood pressure will be monitored in the chronic study procedure by means of a radiotransmitter.
The radiotransmitter is surgically impianied intc the abdominal acta ¢f rats, pricr io the initiation of DOCA-salt treatment and thus, prior to the induction of hypertension. Blood pressure is chronically monitored for periods of up 6 weeks (approximately one week prior to
DOCA-salt administration and for 5 weeks thereafter).
Rats are anesthetized with 2-3% isoflurane in oxygen inhalant followed by Amytal sodium (amobarbital) 100 mg/kg, ip. The level of anesthesia is assessed by a steady rhythmic breathing pattern.
Acute study procedure:
Rats undergo a unilateral nephrectomy at the time of DOCA implantation. Hair is clipped on the left flank and the back of the neck and scrubbed with sterile alcohol swabs and povidonefiodine. During surgery rats are placed on a heating pad to maintain body temperature at 37 °C.
A 20 mm incisicr is made through the skin and underiying muscie to expose the ieft kidney.
The kidney is freed of surrounding tissue, exteriorized and two ligatures (3-0 silk) are tied securely around the renal artery and vein proximal to their juncture with the aorta. The renal artery and vein are then severed and the kidney removed. The muscle and skin wounds are closed with 4-0 silk suture and stainless steel wound clips, respectively. At the same time, a mm incision is made on the back of the neck and a 3-week-release pellet (Innovative
Research of America, Sarasota, Florida) containing deoxycorticosterone acetate (100 mg/kg) is implanted subcutaneously. The wound is then closed with stainless-steel clips and both wounds are treated with povidone/iodine; the rats are given a post-surgical intramuscular injection of procaine penicillin G (100,000 U) and buprenorphine (0.05 ~ 0.1 mg/kg) s.c. The rats are immediately placed on 1% NaCl + 0.2% KCI drinking water; this treatment continues for at least 3 weeks at which time the animals have become . hypertensive and available for experimentation. : Forty-eight hours prior to experimentation, animals are anesthetized with isoflurane and catheters are :mpianted ir: the femoral artery anc veir: for measuring arterial pressure, collection of blood, and administration of test compounds. Rats are allowed to recover for 48

Claims (20)

What is claimed is:
1. A pharmaceutical composition comprising (i) an angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, (i) a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, and (iy a diuretic or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition according to claim 1, wherein (i) the angiotensin receptor blocker (ARB) is selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, oimesartan, saprisartan, tasosartan, telmisartan, valsartan, E-4177, SC-52458, and ZD8731; (ii) the calcium channel blocker (CCB) is selected from the group consisting of amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, rycsidine, anipamil, diltiazem, fendiline, flunarizine, gallocamil, mibefradil, prenylamine, tiapamil, and verapamil; and (iii) the diuretic is selected from the group consisting of bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, spironolactone, triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyichlorothiazide, metolazone, and dichlorphenamide.
3. A pharmaceutical composition according to claim 2, wherein (i) the angiotensin receptor blocker (ARB) is valsartan; (ii) the calcium channel blocker (CCB) is amlodipine; and (iii) the diuretic is hydrochlorothiazide.
4. A pharmaceutical composition according to claim 3, wherein valsartan is contained in an amount from about 20 to about 640 mg, amlodipine is contained in an amount from : about 1 mg to about 60 mg, and hydrochlorothiazide is contained in an amount from about 5 mg to about 200 mg.
5. A pharmaceutical composition according to ciaim 4, wherein vaisartan is contained in an amount from about 40 to about 320 mg, amlodipine is contained in an amount from about 2.5 mg to about 10 mg, and hydrochlorothiazide is contained in an amount from about 5 mg tc about 25 mg.
+ 6. Akit of parts comprising (i) a pharmaceutical composition of an angiotensin receptor blocker (ARB), (ii) a pharmaceutical composition of a calcium channel blocker (CCB), and (iii) a pharmaceutical composition of a diuretic in the form of two or three separate units of the components (i) to (iii).
7. Akit of parts according to claim 6, wherein (i) the angiotensin recepror blocker (ARB) is selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, teimisartan, valsartan, E-4177, SC-52458, and ZD8731; (ii) the calcium channel blocker (CCB) is selected from the group consisting of amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, ryosidine, anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamine, tiapamil, and verapamii; and (iii) the diuretic is seiected from the group consisting of bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, spironolactone, triamterene, chlorothalidone, chiorothiazide, hydrochliorothiazide, hydroflumethiazide, methyichlorothiazide, metolazone, and dichlorphenamide.
8. A kit of parts according to claim 7, wherein (i) the angiotensin receptor blocker (ARB) is valsartan; (ii) the calcium channel blocker (CCB) is amlodipine; and (iii} the diuretic is hydrochlorothiazide.
9. A Kit of parts according to claim 8, wherein valsartan is contained in an amount from about 20 to about 640 mg, amlodipine ins contained in an amount from about 1 mg to about 60 mg, and hydrochiorothiazide is contained in an amount from about 5 mg to : about 200 mg. : 10. A kit of parts according to claim 9, wherein valsartan is contained in an amount from about 4G to about 320 mg, amlodipine ins contained in an amount from about 2.5 mg to about 10 mg, and hydrochlorothiazide is contained in an amount from about 5 mg to about 25 mg.
Case 4-32495A
11. A pharmaceutical composition comprising a combination of (i) an ARB selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan, E-4177, SC-52458, and ZD8731, ora pharmaceutically acceptable salt thereof; and (ii) a CCB selected from the group consisting of amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, and ryosidine, which all belong to the group of dihydropyridines (DHPs) and the non-DHP CCBs anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamine, tiapamil, and verapamil, or a pharmaceutically acceptable salt thereof; and (iii) a diuretic selected from the group consisting of bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, spironolactone triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyichlorothiazide, metolazone, and dichlorphenamide, or, where appropriate, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in the treatment or preventior of g condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Aizheimer’s), glaucoma and stroke.
12. A commercial package comprising (i) a pharmaceutical comnogition af z= 2ngictsneln r3cesicr coker RTat=)N (i) a pharmaceutical composition of a caicium channei blocker (CCB), and (iii) a pharmaceutical composition. cf a diuretic, in the form of two or three separate units of the components (i) to (iii),
together with instructions for simultaneous, separate or sequential use thereof for the treatment or prevention of a condition or disease seiecied from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke
13. A commercial package according to ciaim 12, wherein (i) the angiotensin receptor blocker {ARR) is valsartan; {ii} the calcium channel blocker (CCB) is amiodipine; and (iii) the diuretic is hydrochlorothiazide.
14. A commercial package according to claim 13, wherein the angiotensin receptor blocker (ARB) (i) and the diuretic (iii) are present in the form of Co-DIOVAN ® or wherein the angiotensin receptor blocker (ARB) (i), the CCB (ii) and the diuretic (iii) are present in the form of Co-DIOVAN ® and Norvasc ®.
15. The use of a combination according to any one of claims 1 to 5, or a kit of parts according to any one of claims 6 to 10, for the manufacture of a medicament for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left
. ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricuiar and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental : vascular remodeling, mvocardial infarction and its sequelae, atherosclerosis, angina ‘whether unstable or stabie}, renai insufficiency {diabetic and non- diabetic), heart failure, angina pectoris, diabetes, secondary aidecsteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy,
Case 4-32495A glomerulonephritis, scleroderma, glomerular scierosis, proteinuria of primary renal disease, and also renal vascu'ar hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), glaucoma and stroke.
16. The use of a combination according to any cre of claims 1 to 5, crakitof pars according to any one of claims 6 to 10, for the treatment or prevention of a condition or disease seiected from the group ccrsisting of hypertersicn, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardicmyogathy, diabetic cardiac mycpathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial fdutter, detrimental vascular remodeling, myocardial infarction and its sequeize, atherosclerosis, angira {whether unstabie or stable], renal insufficiency ‘abgots and nan. diabells), haat fails, angina gectoris, diabetes, sccerdary aldosteronism, primary and secendary pu!menary hypertensicn, renal failure conditions, such as diabetic nephropathy, glomerulcnepkritis, scleroderma, glomerular sclercsis, proteinuria of primary reral disease, and aiso renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfurction (such as Alzheimer's), glaticoma and stroke. i» ; i i ir ribed
17. A pharmaceutical composition according to claim 1, substantially as herein desc and exemplified.
. ; rol i ifi
18. AKkit according to claim 6, substantially as herein described and exemplified
, . i i i ified.
19. Use according to claim 15 or 16, substantially as herein described and exempli ) : a ra ial! herein i] ; and
20. A commerciai package according to claim 12, substantially as herein described a exemplified.
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US6395728B2 (en) 1999-07-08 2002-05-28 Novartis Ag Method of treatment and pharmaceutical composition
CN1301545A (en) 1999-12-27 2001-07-04 王德山 Compound depressor
DE10004651A1 (en) 2000-02-03 2001-08-16 Jutta Dierkes Combination of antihypertensive agents with drugs that reduce homocysteine levels
AU2001289672B2 (en) 2000-07-19 2005-12-08 Novartis Ag Valsartan salts
CA2430924A1 (en) 2000-12-01 2002-06-06 Novartis Ag Angiotensin receptor antagonist composition for the treatment of sexual dysfunction associated with hypertension and another condition
EG24716A (en) 2002-05-17 2010-06-07 Novartis Ag Combination of organic compounds
GT200600371A (en) 2005-08-17 2007-03-21 SOLID DOSE FORMS OF VALSARTAN AND AMLODIPINE AND METHOD TO DO THE SAME

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